Abstract
Clozapine (CLZ) has been proposed as an agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), to replace Clozapine-N-oxide (CNO); however, there are no reliable guidelines for the use of CLZ for chemogenetic neuromodulation. We titrated the optimal dose of CLZ required to evoke changes in neural activity whilst avoiding off-target effects. We also performed [18F]Fluoro-deoxy-glucose micro positron emission tomography (FDG-microPET) scans to determine the global effect of CLZ-induced hM3D(Gq) DREADD activation in the rat brain. Our results show that low doses of CLZ (0.1 and 0.01 mg/kg) successfully induced neural responses without off-target effects. CLZ at 1 mg/kg evoked a stronger and longer-lasting neural response but produced off-target effects, observed as changes in locomotor behavior and FDG-microPET imaging. Unexpectedly, FDG-microPET imaging failed to demonstrate an increase in regional glucose metabolism in the stimulated cortex during CLZ chemogenetic neuromodulation. Therefore, caution should be used when interpreting FDG-PET images in the context of cortical chemogenetic activation.
Highlights
Neuroscientists and neurologists have long dreamed of being able to use non-invasive, target-specific neuromodulators; such tools can be relatively translated to treat neurological disorders
Given that CLZ induces metabolic depression in multiple areas of the brain including the basal ganglia, thalamus, and cortical areas, and consequent changes in behavior[12,26], we first explored the dose-dependent effects of CLZ in naive rats using [18F]Fluoro-deoxy-glucose micro positron emission tomography (FDG-microPET) and the open field test
We evaluated the effects of CLZ-ChemoNM via the hM3D(Gq) Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on locomotor activity, spike firing, and FDG-PET imaging to validate the usefulness of this tool for future ongoing experiments
Summary
Neuroscientists and neurologists have long dreamed of being able to use non-invasive, target-specific neuromodulators; such tools can be relatively translated to treat neurological disorders. Given that CLZ induces metabolic depression in multiple areas of the brain including the basal ganglia, thalamus, and cortical areas, and consequent changes in behavior[12,26], we first explored the dose-dependent effects of CLZ in naive rats (i.e., rats not expressing DREADDs) using [18F]Fluoro-deoxy-glucose micro positron emission tomography (FDG-microPET) and the open field test. In both naive and virus-expressed rats, administration of saline did not produce any significant changes in rGluM in somatosensory cortex
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